Programmed cell death controlled embryologically or physiologically can be observed in all most tissues of various animals. Such programmed cell death is generally called, “Programmed cell death” or “Premeditated programmed cell death”, and distinguished from “unexpected cell death” which could be caused by a pathologic mechanism.
First, PD-1 has been found in mice as a receptor that cells are related to process to premeditated programmed cell death through the activation (The EMBO J., vol. 11(11), 3887-3895(1992); JP05-336973; EMBL/GenBank/DDJB Acc. No.X67914). Then, it has been found in human by using the gene of mouse PD-1 as a probe (Genomics 23:704 (1994); JP07-291996). Because PD-1 has expressed in lymphocytes with activation and has deeply related to autoimmune disease by researches of PD-1 deficient mice (International Immunology, Vol. 10(10), 1563-1572(1998); Immunity. Vol. 11, 141-151(1999)), it has been suggested to be used for treatments and diagnoses of decrease or accentuation of immune function, infectious disease, rejections in transplant and tumours, etc. Both mouse and human PD-1 are composed by 288 amino acids, and are type I membrane-bound 55 kDa proteins with the hydrophobic region in the penetrative area of the cell-membrane in the middle and the signal peptide (20 amino-acids) in the N-terminus. Deficient mice (called the knockout mice.) are indicated those which cannot produce the gene product in born by modifying a specific gene artificially, and are made to examine roles of factors and receptors that are the gene products.
However, dilated cardiomyopathy indicates the contractile dysfunction of left ventricle with the dilatation of left ventricular. Though 30% of patients considered to be dilated cardiomyopathy are assumed to be caused by inherent mutations in the structural gene to code the key component of heart muscle, which connects intracellular cytoskeleton with intercellular matrix, the remaining cases remain uncertain. In both cases, the disease is progress, and threatens the life, and there is no available treatment method excluding cardiac transplant now.
First, PD-1 deficient mice were made with C57BL/6 (Hereafter, omit it with B6) mice. It has been confirmed that PD-1 deficient C57BL/6 mice naturally developed so-called autoimmune disease such as lupus nephritis and arthritis, etc. (International Immunology, Vol. 10(10), 1563-1572(1998); Immunity. Vol. 11, 141-151(1999)).
However, it really has been not known to what influence the difference of the genetic background influences the loss of PD-1, in case that PD-1 is lacked in other strain mice.